The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children Research Institute, University of Toronto, Toronto, Ontario, Canada.
J Exp Med. 2011 Feb 14;208(2):313-26. doi: 10.1084/jem.20101470. Epub 2011 Jan 17.
Proliferating embryonic and cancer cells preferentially use aerobic glycolysis to support growth, a metabolic alteration commonly referred to as the "Warburg effect." Here, we show that the glycolytic enzyme hexokinase 2 (HK2) is crucial for the Warburg effect in human glioblastoma multiforme (GBM), the most common malignant brain tumor. In contrast to normal brain and low-grade gliomas, which express predominantly HK1, GBMs show increased HK2 expression. HK2 expression correlates with worse overall survival of GBM patients. Depletion of HK2, but neither HK1 nor pyruvate kinase M2, in GBM cells restored oxidative glucose metabolism and increased sensitivity to cell death inducers such as radiation and temozolomide. Intracranial xenografts of HK2-depleted GBM cells showed decreased proliferation and angiogenesis, but increased invasion, as well as diminished expression of hypoxia inducible factor 1α and vascular endothelial growth factor. In contrast, exogenous HK2 expression in GBM cells led to increased proliferation, therapeutic resistance, and intracranial growth. Growth was dependent on both glucose phosphorylation and mitochondrial translocation mediated by AKT signaling, which is often aberrantly activated in GBMs. Collectively, these findings suggest that therapeutic strategies to modulate the Warburg effect, such as targeting of HK2, may interfere with growth and therapeutic sensitivity of some GBMs.
胚胎和癌细胞优先通过有氧糖酵解来支持生长，这种代谢改变通常被称为“瓦博格效应”。在这里，我们表明，糖酵解酶己糖激酶 2（HK2）对于人类多形性胶质母细胞瘤（GBM）中的瓦博格效应至关重要，GBM 是最常见的恶性脑肿瘤。与表达主要为 HK1 的正常大脑和低级别神经胶质瘤不同，GBM 中 HK2 的表达增加。HK2 的表达与 GBM 患者的总体生存率降低相关。在 GBM 细胞中耗尽 HK2，但不是 HK1 或丙酮酸激酶 M2，可恢复氧化葡萄糖代谢，并增加对辐射和替莫唑胺等细胞死亡诱导剂的敏感性。HK2 耗尽的 GBM 细胞颅内异种移植物显示出增殖和血管生成减少，但侵袭性增加，以及缺氧诱导因子 1α和血管内皮生长因子的表达减少。相比之下，GBM 细胞中外源 HK2 的表达导致增殖、治疗耐药性和颅内生长增加。生长依赖于 AKT 信号转导介导的葡萄糖磷酸化和线粒体易位，AKT 信号转导在 GBM 中经常异常激活。总的来说，这些发现表明，调节瓦博格效应的治疗策略，如靶向 HK2，可能会干扰某些 GBM 的生长和治疗敏感性。
